CN117342570A - A crystal form A of sodium zirconium cyclosilicate and its preparation method - Google Patents

Abstract

The invention discloses an A crystal form of sodium zirconium silicate and a preparation method thereof, and relates to the technical field of pharmacy. The X-ray powder diffraction pattern of the crystal form has characteristic diffraction peaks at angles of 10.63+/-0.2 degrees, 12.24+/-0.2 degrees, 13.89+/-0.2 degrees, 14.62+/-0.2 degrees, 15.24+/-0.2 degrees, 15.55+/-0.2 degrees, 17.86+/-0.2 degrees, 21.48+/-0.2 degrees, 21.93+/-0.2 degrees, 25.55+/-0.2 degrees, 26.18+/-0.2 degrees, 28.88 +/-0.2 degrees, 29.52+/-0.2 degrees, 30.19+/-0.2 degrees and 36.19+/-0.2 degrees. The crystal form A of the sodium zirconium silicate has physicochemical properties similar to those of a reference preparation (ZS-9 crystal form), the preparation method has no special process conditions such as high temperature, high pressure and the like, no special reaction equipment is needed, the cost is low, and the large-scale production is easy.

Description

A crystal form A of sodium zirconium cyclosilicate and its preparation method

Technical field

The present invention relates to the field of pharmaceutical technology, and in particular to a crystal form A of sodium zirconium cyclosilicate and a preparation method thereof.

Background technique

Hyperkalemia is a common electrolyte imbalance in the body, which can be life-threatening in severe cases. It is more common in patients with chronic kidney disease (CKD) and heart failure. Currently, CKD has a high incidence rate worldwide, and elevated blood potassium in the body will accelerate the disease progression of CKD patients, leading to many adverse consequences such as emergency hospitalization, increasing the risk of death, and hyperkalemia is prone to recurring and persistent occurrences. , bringing psychological pressure and financial burden to patients and their families. Sodium zirconium cyclosilicate is an inorganic crystal and is a recently marketed potassium-lowering drug (launched in the United States and China in 2018 and 2019). It has a unique cubic crystal structure and has high binding force for potassium ions. It binds to potassium ions in the intestines and is excreted in the feces, thereby lowering blood potassium levels.

Patent US5891417 was the first to disclose sodium zirconium cyclosilicate, and it has different crystal forms of ZS-1 to ZS-11. The patent CN1061708831 of the original research company disclosed that among the various crystal forms of ZS-1 to ZS-11 of sodium zirconium cyclosilicate, ZS-9 has a higher potassium ion exchange capacity and can significantly improve the potassium ion absorption characteristics and Rapid decrease in elevated levels of serum potassium.

Chinese patent CN109106725A discloses microporous zirconium silicate for the treatment of hyperkalemia, and also discloses a method for preparing high-purity crystals of ZS9 that exhibit increased potassium exchange capacity levels. In its preparation method, a hydrothermal reaction at 200°C is required for 72 hours, and the reaction conditions are relatively harsh.

Chinese patent CN108137620A discloses a zirconium silicate composition with a lead content of less than 0.6 ppm, and a method of manufacturing zirconium silicate with a lead content of less than 1.1 ppm with a reactor volume exceeding 200L. During its preparation, the reactor was maintained at 210±5°C for at least 36 hours.

The preparation process conditions for sodium zirconium cyclosilicate of the ZS-9 crystal form in the existing technologies that have been retrieved (including CN109106725A, CN108137620A, IN202041056388A and IN201941046191A, etc.) are relatively harsh, such as high temperature and pressure above 200°C. It needs to be above 2.5MPa and requires special reaction equipment (such as adding baffles to the inner wall of the reactor), making it difficult to achieve large-scale industrial production.

Therefore, in order to increase the selection of raw materials for sodium zirconium cyclosilicate preparations, a new drug is needed that has similar potassium ion exchange capacity and other physical and chemical properties to ZS-9, has a low-cost preparation method, and is easy to achieve large-scale production. Crystalline form of sodium zirconium cyclosilicate.

Contents of the invention

In view of this, the object of the present invention is to provide a new crystal form of sodium zirconium cyclosilicate (named crystal form A) and its preparation method. The preparation reaction conditions of this crystal form are mild, no special reaction equipment is required, and the cost is low. Easier to achieve large-scale production.

In order to achieve the above-mentioned object of the invention, the technical solutions of the present invention are as follows:

On the one hand, the present invention provides a crystal form of sodium zirconium cyclosilicate. The X-ray powder diffraction pattern of the crystal form is at 2θ angles of 10.63±0.2°, 12.24±0.2°, 13.89±0.2°, and 14.62±0.2°. ,15.24±0.2°,

15.55±0.2°, 17.86±0.2°, 21.48±0.2°, 21.93±0.2°, 25.55±0.2°, 26.18±0.2°,

There are characteristic diffraction peaks at 28.88±0.2°, 29.52±0.2°, 30.19±0.2°, and 36.19±0.2°.

Further, the infrared spectrum of the crystal form has absorption wave numbers of 1121±5cm ^-1 , 967±5cm ^-1 , 773±5cm ^-1 , 444±5cm ^-1 , 541±5cm ^-1 , and 489±5cm ^-1 Characteristic absorption peaks.

On the other hand, the present invention provides a method for preparing the crystal form of the above-mentioned sodium zirconium cyclosilicate, which includes the following steps:

(1) Mix the sodium silicate solution and the alkali solution, add the zirconium-containing solution dropwise, and mix;

(2) Heat to reflux;

(3) After the reaction is completed, cool;

(4) Filter and wash until pH is 7-9;

(5) Dry to obtain the crystalline sodium zirconium cyclosilicate.

Preferably, the molar ratio of sodium silicate, alkali and zirconium is 1:3.5-6:3-5, most preferably 1:4.4:4.

Preferably, the concentration of the sodium silicate solution is 70-85%, most preferably 77.7%; the concentration of the alkali solution is 5-10%, most preferably 7.2%; the concentration of the zirconium-containing solution is 50-70%, most preferably 60%.

Preferably, in step (1), the base is selected from sodium hydroxide, potassium hydroxide, barium hydroxide, ammonium hydroxide, calcium hydroxide, sodium methoxide, potassium ethoxide, potassium tert-butoxide, butyllithium, benzene At least one of the lithium bases is more preferably at least one of sodium hydroxide, potassium hydroxide, and barium hydroxide, and most preferably is sodium hydroxide.

Preferably, in step (1), the zirconium-containing solution is selected from at least one of zirconium acetate solution and zirconium carbonate solution, and is further preferably zirconium acetate solution.

Preferably, in step (3), the reaction time is 1-9 days.

Preferably, in step (3), the cooling temperature is 30°C or lower, and more preferably room temperature.

Preferably, in step (5), the drying refers to drying under reduced pressure, more preferably drying under reduced pressure at 80-150°C, and even more preferably drying under reduced pressure at 100°C for 24 hours.

The beneficial effects of the present invention are:

The sodium zirconium cyclosilicate A crystal form obtained by the present invention has potassium ion exchange capacity and other physical and chemical properties similar to the reference preparation (ZS-9 crystal form), which expands the selection range of raw materials for sodium zirconium cyclosilicate preparations. , the preparation method of the crystal form invented does not require special process conditions such as high temperature and high pressure, does not require special reaction equipment, is low in cost, and is easier to achieve large-scale production.

Description of drawings

Figure 1 is an XRD pattern of sodium zirconium cyclosilicate of crystal form A prepared by the present invention.

Figure 2 is an IR diagram of sodium zirconium cyclosilicate of crystal form A prepared by the present invention.

Detailed ways

The following non-limiting examples can enable those of ordinary skill in the art to understand the present invention more comprehensively, but do not limit the present invention in any way. The following content is only an illustrative description of the scope of protection of the present invention. Those skilled in the art can make various changes and modifications to the invention of the present invention based on the disclosed content, and they should also fall within the scope of protection of the present invention. .

The present invention will be further described below in the form of specific examples. Various chemical reagents used in the examples of the present invention were obtained through conventional commercial channels unless otherwise specified. Unless otherwise specified, the contents stated below are mass contents. If there is no special instructions, it is understood that it is carried out at room temperature.

In the following examples, the source of reference preparation ZS-9: AatraZeneca, batch number: MK2232A;

The concentration of sodium hydroxide solution is 7.2%, the concentration of zirconium acetate solution is 60%, and the concentration of sodium silicate solution is 37.7%;

XRD testing machine brand model:

Infrared detection machine brand model:

Potassium ion exchange capacity (KEC) testing instrument brand model:

Example 1

In a 1L four-neck glass reaction flask, add 206g sodium silicate solution, add 377g sodium hydroxide solution, stir for 5-10 minutes, add 82g zirconium acetate solution dropwise, the molar ratio of sodium silicate, alkali, and zirconium is 1:4.4: 4. After the dripping is completed, stir for 5 to 10 minutes, heat to reflux, and monitor the reaction progress with online infrared (the reaction ends about 7 days later). After the reaction is completed, cool to room temperature, filter, and wash with purified water until the filtrate pH=7 to 9 to obtain a ring. Sodium zirconium silicate wet product, dry the wet product under reduced pressure at 100°C for 24 hours to obtain crystal form A of sodium zirconium cyclosilicate.

The XRD detection pattern is shown in Figure 1, and the infrared spectrum is shown in Figure 2.

The potassium ion exchange capacity detection results of the sodium zirconium cyclosilicate of crystal form A obtained in this example are compared with the reference preparation. The results are as follows:

project A crystal form Reference preparation (ZS-9) Potassium ion exchange capacity 3.1 3.2

Comparison shows that the sodium zirconium cyclosilicate A crystal form obtained by the present invention has a potassium ion exchange capacity similar to that of the reference preparation (ZS-9 crystal form), and does not require special process conditions such as high temperature and high pressure, and does not require special reaction equipment and low cost. Cheap and easier to achieve large-scale production.

The above descriptions are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the present invention. within the scope of protection.

Claims (10)

1. A crystal form of sodium zirconium cyclosilicate, characterized in that the X-ray powder diffraction pattern of the crystal form is at 2θ angles of 10.63±0.2°, 12.24±0.2°, 13.89±0.2°, and 14.62±0.2°. , 15.24±0.2°, 15.55±0.2°, 17.86±0.2°, 21.48±0.2°, 21.93±0.2°, 25.55±0.2°, 26.18±0.2°, 28.88±0.2°, 29.52±0.2°, 30.19±0.2° , there is a characteristic diffraction peak at 36.19±0.2°. 2. The crystal form of sodium zirconium cyclosilicate according to claim 1, characterized in that the infrared spectrum of the crystal form has absorption wave numbers of 1121±5cm ^-1 , 967±5cm ^-1 , 773±5cm ^-1 , There are characteristic absorption peaks at 444±5cm ^-1 , 541±5cm ^-1 and 489±5cm ^-1 . 3. The preparation method of the crystal form of sodium zirconium cyclosilicate according to claim 1 or 2, characterized in that it includes the following steps: (1) Mix the sodium silicate solution and the alkali solution, add the zirconium-containing solution dropwise, and mix; (2) Heat to reflux; (3) After the reaction is completed, cool; (4) Filter and wash until pH is 7-9; (5) Dry to obtain the crystalline sodium zirconium cyclosilicate. 4. The method for preparing the crystal form of sodium zirconium cyclosilicate according to claim 3, characterized in that the molar ratio of sodium silicate, alkali and zirconium is 1:3.5-6:3-5. 5. The method for preparing the crystal form of sodium zirconium cyclosilicate according to claim 4, characterized in that the molar ratio of sodium silicate, alkali and zirconium is 1:4.4:4. 6. The preparation method of the crystal form of sodium zirconium cyclosilicate according to claim 3, characterized in that the concentration of the sodium silicate solution is 70-85%; the concentration of the alkali solution is 5-10%; and the concentration of the zirconium-containing solution is 50-70%. 7. The preparation method of the crystal form of sodium zirconium cyclosilicate according to claim 3, characterized in that, in step (1), the alkali is selected from the group consisting of sodium hydroxide, potassium hydroxide, barium hydroxide, and ammonium hydroxide. , at least one of calcium hydroxide, sodium methoxide, potassium ethoxide, potassium tert-butoxide, butyllithium, and phenyllithium; the zirconium-containing solution is selected from at least one of zirconium acetate solution and zirconium carbonate solution. 8. The method for preparing the crystal form of sodium zirconium cyclosilicate according to claim 7, wherein the alkali is sodium hydroxide; and the zirconium-containing solution is a zirconium acetate solution. 9. The method for preparing the crystal form of sodium zirconium cyclosilicate according to claim 3, characterized in that in step (3), the reaction time is 1-9 days. 10. The method for preparing the crystal form of sodium zirconium cyclosilicate according to claim 3, characterized in that in step (3), the cooling temperature is 30°C or less.